Handbook of Genetic Counseling/Neurofibromatosis - Type 1

Neurofibromatosis - Type 1


  • What is your understanding about why you were referred to genetics?
  • What are your main concerns or questions?
  • Outline session
    • I will first ask you some questions about your family history and _____'s medical history
    • Then Dr. _____ will examine ______
    • We will discuss what we know at that point about whether or not a diagnosis can be made and we will answer any questions you might have.

Elicit Family HistoryEdit

  • Family history can be helpful in determining if there is something in the family that might be inherited
  • Some of the things I'm looking for in your family history include:
    • Birth defects
    • History of pregnancy losses
    • learning difficulties or MR
    • chronic health problems
    • unusual skin findings or birth marks
    • hearing loss
    • underarm freckling
    • scoliosis
    • seizures
    • vision loss
    • anyone who died at a young age or unexpectedly
    • Anything else that you think might be running in your family

Incidence of NF1Edit

  • NF1 is estimated to affect 1/3,500 people in the population
  • Affects both sexes and all racial and ethnic groups equally

Clinical FeaturesEdit

  • Clinical features are extremely variable both between and within families
  • Not all of the features are present in individuals with NF1
  • Skin:
    • Café-au-lait spots in ~94% of patients
    • Axillary or inguinal freckling- common after 3 years of age
    • Xanthogranulomas (2-5%)
    • Hemangiomas (5-10%)
  • Eye:
    • Optic glioma (often present at birth; occurs in 10-15% of patients)
    • Lisch nodules- pigmented iris hamartomas (100% after the age of 20)
  • Tumors
    • Neurofibromas- benign tumors arising from nerve cells that can occur anywhere in the body and are often associated with the skin.
    • Plexiform neurofibromas- tumors along nerve bundle tracts, can be large and usually appear at birth or early in childhood (occur in ~25%)
    • Malignant peripheral nerve sheath tumors arise in ~2-4% of individuals
    • Pheocromocytoma, rhabdomyoma, neuroblastoma (rare)
    • Myelogenous leukemia (rare)
  • Neurological:
    • Headaches occur in >10% of patients
    • Seizures and/or EEG abnormalities occur in ~20%
    • Seizures 6-7%
    • Hydrocephalus occurs in ~5% of individuals
    • Sensorineural hearing loss occurs in ~5% of patients
    • Precocious puberty (2-5%)
  • Orthopedic:
    • Scoliosis
    • Hypoplastic bowing of lower legs, with pseudoarthrosis at birth
    • Short stature
    • Macrocephaly
  • Cardiovascular:
    • Hypertension (2-5%)
    • Congenital heart defect (2%)
  • Cognitive:
    • Developmental delay
    • Learning disabilities- hyperactivity and/or speech problems occur in 50%
    • Mental retardation (8% of patients)
  • Other-occasional:
    • Syndactyly
    • Glaucoma
    • Ptosis
    • Pruritis

Diagnostic CriteriaEdit

(clinical diagnosis based on a number of clinical findings)

  • NF1 is present in an individual who has two or more of the following signs:
    • Six or more café au lait macules >5 mm in prepubertal individuals or >15 mm after puberty
    • Two or more neurofibromas of any type, or one+ plexiform neurofibromas
    • Freckling in the axilla or inguinal regions
    • A tumor of the optic pathway (optic glioma)
    • Two or more Lisch nodules
    • Long bone bowing (w/ or w/o pseudarthrosis)
    • A first-degree relative with NF1 by the above criteria

Natural History and Life Span: NF1Edit

  • Although the medical literature and the internet tend to show the most severe cases, approximately 2/3 have only mild or moderate involvement throughout their lifespan
  • Lifespan is dependent on severity and types of symptoms, but it has been shown in one study that the average life expectancy of patients with NF1 can be reduced by at least 15 years overall
  • Decreased lifespan has been associated with the following features:
    • Malignant peripheral sheath tumors
    • Acute hydrocephalus
    • Severe seizure
    • Progressive spinal plexiform neurofibromas
  • Frequency of more serious complications increases with age
  • Various manifestations of NF1 have different characteristic times of appearance
  • Since characteristic features often develop with age, if NF1 is suspected it is often necessary to continue to follow them for a while before the diagnosis can be ruled out completely
  • Infancy:
    • Café-au-lait spots
    • Long bone bowing
    • Developmental delay
    • Optic glioma
    • Plexiform neurofibroma
  • Childhood:
    • Neurofibromas
    • Freckling patterns
    • Learning disabilities
    • Scoliosis
    • Hypertension
  • Adolescence:
    • Worsening of existing condition
    • Rarely malignant peripheral nerve sheath tumors develop
  • Adulthood:
    • Increase in neurofibromas
    • Hypertension
    • If other symptoms have not developed, they may do so at this time
  • Pregnancy:
    • most pregnancies in women with NF1 are normal but serious complications can occur
    • Many women with NF1 experience a rapid increase in the number and size of neurofibromas during pregnancy
    • Hypertension may first become symptomatic or, if pre-existing, may become worse
    • Large pelvic or genital neurofibromas can complicate delivery
    • cesarean section appears to be necessary more often in pregnant women with NF1 than in other women.


    • NF1 gene located on long arm of chromosome 17q11.2
    • NF1 gene is classified as a tumor suppressor gene, however the gene has other functions that are not as well defined
    • In about 50% of individuals with NF 1 it was inherited from an affected parent and the other half are due to a new mutation not already present in the family
    • If a person has this gene they will almost certainly show some signs or characteristics, but these may not be obvious and it is possible for a person to go undiagnosed (nearly 100% penetrant, but variable expressivity)
    • The gene is very large which is consistent with the number of patients with NF1 that were due to a new mutation
    • Gene encodes for a protein called neurofibromin (believed to act as tumor suppressor, but probably also has other functions)
  • Autosomal Dominant inheritance
    • Autosomal means it is on a chromosome other than sex chromosome
    • Dominant means only one altered copy of this gene is necessary to develop symptoms and characteristics
  • Risk assessment:
    • For affected individuals 50% risk for each pregnancy to be affected, although clinical expression is variable
    • For unaffected parents the recurrence risk is (<1%) (germline mosaicism in one man reported)

Provide patient literatureEdit


  • Families with two or more affected individuals can use linkage analysis to identify carriers of the disease causing NF1 gene
  • Sporadic cases require direct mutational analysis of the gene, if presymptomatic testing is desired
  • DNA testing by protein truncation is available but rarely used for diagnosis (reported to detect 70% of mutations, but not firmly established)
  • Mutation may be missed due to large size of gene and many mutations possible
  • FISH can be used to detect microdeletions of chromosome 17q11.2
  • Individuals with large deletions tend to have mental retardation and an increased tumor burden (approximately 5% of individuals with NF1 have whole gene deletions)

Prenatal testingEdit

  • Possible if there is a known mutation or via linkage studies if enough affected family members
  • It is not often used

Genotype/phenotype correlationEdit

  • Differences seen even in members of same family suggest some randomness to some of features.
  • Two-hit hypothesis supports these findings
  • However, there are some similarities of phenotype seen in

Management and Treatment OptionsEdit

  • Individuals should be placed on surveillance programs
    • Annual physical examination by a physician who is familiar with NF1
    • Annual ophthalmological examination in childhood, less frequent examination in adults
    • Regular developmental assessment by screening questionnaire
    • Regular blood pressure monitoring
    • Other studies only as indicated on the basis of clinically apparent signs or symptoms (HOWEVER, some centers do MRI on newly diagnosed patients though)
  • Treatment includes treating the symptoms as they occur
    • Learning difficulties: appropriate school placement, IEP
    • Dermal neurofibromas: surgically remove if they are symptomatic
    • Early recognition of long bone bowing can be accompanied with braces (which may help prevent fractures)
    • MRI's should be scheduled to screen for optic gliomas
    • Ophthalmologic exam to look for Lisch nodules
    • Bracing for scoliosis
    • Meds for seizures and headaches

Differential DiagnosisEdit

  • Overlap primarily lies in cutaneous features, especially café-au-lait spots
  • Neurofibromatosis 2 (bilateral acoustic neuromas, tumors of cranial nerves and spinal roots, skin manifestations less frequent than in NF1)
  • Multiple café-au-lait spots (an autosomal dominant trait without other features of neurofibromatosis)
  • LEOPARD syndrome (multiple lentigines, ocular hypertelorism, deafness, congenital heart disease)
  • McCune-Albright syndrome (large café-au-lait spots with irregular margins, polyostotic fibrous dysplasia)
  • Noonan syndrome (short stature, unusual facies, pulmonic stenosis)
    • A Noonan syndrome phenotype occurs in about 12% of patients with NF1 and features may include ocular hypertelorism, down-slanting palpebral fissures, low-set ears, webbed neck, and pulmonic stenosis
  • Multiple endocrine neoplasia type 2B (mucosal neuromas, conjunctival neuromas, pheochromocytoma, medullary carcinoma of the thyroid, marfanoid habitus)
  • Multiple lipomatosis (multiple cutaneous lipomas)
  • Bannayan-Ruvalcaba-Riley syndrome (multiple lipomas and hemangiomas, macrocephaly, spotted pigmentation of the glans penis).
  • Juvenile hyaline fibromatosis (multiple subcutaneous tumors, gingival fibromatosis)
  • Congenital generalized fibromatosis (multiple tumors of the skin, subcutaneous tissues, skeletal muscle, bones, and viscera) Multiple intradermal nevi (multiple cutaneous tumors)
  • Klippel-Trenaunay-Weber syndrome (cutaneous hemangiomas, varicose veins, aterio-venous fistulas, and hemi-hypertrophy
  • Proteus syndrome (regional overgrowth, hyperpigmentation, multiple lipomas)

Patient resourcesEdit

  • National Neurofibromatosis Foundation
95 Pine Street, 16th Floor
New York, New York 10005
Phone: 212-344-NNFF; 800-323-7938
Fax: 212-747-0004
Email: NNFF@aol.com
Web: www.nf.org
  • Neurofibromatosis, Inc
8855 Annapolis Road, Suite 110
Lanham, MD 20706-2924
Phone: TDD 410-461-5213
Fax: 301-577-0016
Email: nfinc1@aol.com
Web: www.nfinc.org


  • Jones KL (1997). Smith's Recognizable Patterns of Human Malformation.

Philadelphia: W.B. Saunders Company.

  • Viskochil D, Chapter 14. (2001). Management of Genetic Syndromes. Ed. Allanson JE, Cassidy SB. New York: Wiley-Liss, Inc.
  • Gene clinics: www.geneclinics.org


The information in this outline was last updated in 2002.